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The ability to detect recent natural selection in the human population would have profound implications for the study of human history and for medicine. Here, we introduce a framework for detecting the genetic imprint of recent positive selection by analysing long-range haplotypes in human populations. We first identify haplotypes at a locus of interest(More)
BACKGROUND To understand the causal basis of TNF associations with disease, it is necessary to understand the haplotypic structure of this locus. We genotyped 12 single-nucleotide polymorphisms (SNPs) distributed over 4.3 kilobases in 296 healthy, unrelated Gambian and Malawian adults. We generated 592 high-quality haplotypes by integrating family- and(More)
Interleukin-8 (IL8) is believed to play a role in the pathogenesis of bronchiolitis, a common viral disease of infancy, and a recent U.K. family study identified an association between this disease and the IL8-251A allele. In the present study we report data, from a different set of families, which replicate this finding; combined analysis of 194 nuclear(More)
BACKGROUND Severe malaria (SM) is a major cause of death in sub-Saharan Africa. Identification of both specific and sensitive clinical features to predict death is needed to improve clinical management. METHODS A 13-year observational study was conducted from 1997 through 2009 of 2,901 children with SM enrolled at the Royal Victoria Teaching Hospital in(More)
Plasmodium falciparum malaria, an infectious disease caused by a parasitic protozoan, claims the lives of nearly a million children each year in Africa alone and is a top public health concern. Evidence is accumulating that resistance to artemisinin derivatives, the frontline therapy for the asexual blood stage of the infection, is developing in southeast(More)
The objective of this study was to investigate TNF promoter region polymorphisms for association with susceptibility to ankylosing spondylitis (AS). The TNF -238 and -308 polymorphisms were genotyped in 306 English AS cases and 204 ethnically matched healthy B27-positive controls, and 96 southern German AS cases, 58 B27-positive and 251 B27-negative(More)
To assess the hypothesis that nitric oxide is critical in the pathogenesis of cerebral malaria, we analysed genetic variation in the proximal promoter region of NOS2A, the gene encoding inducible nitric oxide synthase. Sequencing 72 Gambian chromosomes revealed 11 single nucleotide polymorphisms in 2.5 kB (theta=8.6 x 10(-4)). Genotyping 104 nuclear(More)
Stimulation of the NF-kappaB pathway often causes p65-p50 and p50-p50 dimers to be simultaneously present in the cell nucleus. A natural polymorphism at nucleotide -863 in the human TNF promoter (encoding tumor necrosis factor [TNF]) region provides an opportunity to dissect the functional interaction of p65-p50 and p50-p50 at a single NF-kappaB binding(More)
The wide variety of disease associations reported at the TNF locus raises the question of how much variation exists within a single population. To address this question, we sequenced the entire TNF gene in 72 chromosomes from healthy residents of a village in The Gambia, West Africa. We found 12 polymorphisms in 4393 nucleotides, of which five have not been(More)
There has been much debate about the relative merits of population- and family-based strategies for testing genetic association, yet there is little empirical data that directly compare the two approaches. Here we compare case-control and transmission/disequilibrium test (TDT) study designs using a well-established genetic association, the protective effect(More)